Comprehensive Characterization of Alternative mRNA Splicing Events in Glioblastoma: Implications for Prognosis, Molecular Subtypes, and Immune Microenvironment Remodeling

Abstract

Alternative splicing (AS) of pre-mRNA has been widely reported to be associated with the progression of malignant tumors. However, a systematic investigation into the prognostic value of AS events in glioblastoma (GBM) is urgently required. The gene expression profile and matched AS events data of GBM patients were obtained from The Cancer Genome Atlas Project (TCGA) and TCGA SpliceSeq database, respectively. 775 AS events were identified as prognostic factors using univariate Cox regression analysis. The least absolute shrinkage and selection operator (LASSO) cox model was performed to narrow down candidate AS events, and a risk score model based on several AS events were developed subsequently. The risk score-based signature was proved as an efficient predictor of overall survival and was closely related to the tumor purity and immunosuppression in GBM. Combined similarity network fusion and consensus clustering (SNF-CC) analysis revealed two distinct GBM subtypes based on the prognostic AS events, and the associations between this novel molecular classification and clinicopathological factors, immune cell infiltration, as well as immunogenic features were further explored. We also constructed a regulatory network to depict the potential mechanisms that how prognostic splicing factors (SFs) regulate splicing patterns in GBM. Finally, a nomogram incorporating AS events signature and other clinical-relevant covariates was built for clinical application. This comprehensive analysis highlights the potential implications for predicting prognosis and clinical management in GBM.

Systemic characterization of alternative splicing related to prognosis, immune infiltration, and drug sensitivity analysis in ovarian cancer

“…With advances in high-throughput technology and the development of next-generation sequencing technologies, it is possible to combine multi-omics databases and use bioinformatics methods to investigate the mechanism of AS behind cancer (49). In order to make all-around and in-depth analysis based on AS events in OV, we focused on constructing an innovative prognostic model to gain more precise survival prediction and combining prognostic AS events with immune infiltration and drug sensitivity analysis to search for more potential therapeutic targets.…”

“…SsGSEA is used to assess the enrichment score of a gene set in each single sample. It can obtain a numerical matrix, which contains the enrichment scores of diverse immune cells in all OV samples (49). The characteristic gene set of immune cells we selected was derived from the study of Charoentong et al (50), which involved in 28 immune cell subsets, including the main cell types related to adaptive and innate immunity.…”

Multi-omics analysis identifies distinct subtypes with clinical relevance in lung adenocarcinoma harboring KEAP1/NFE2L2

“…The SNF method constructs networks of samples for each available genome-wide data and efficiently fuses them into one network, which represents the full spectrum of underlying features and provides a comprehensive view under a given condition [39]. The SNF method has been used and validated in different types of diseases based on multi-omics data [40][41][42][43]. In this study, the SNF method fused all five datasets into one by creating a similarity matrix for each data type.…”

Roles of RNA alternative splicing during the occurrence and development of lung cancer

“…变剪接 [82] 。 LncRNA 的可变剪接在肿瘤的发生和发展过程中同样发挥重要功能 [83,84] 。研究发现，通过可变剪接，人肺腺癌中均可以产生 PD-L1 的一种长链非编 性表型 [85] 。因此 PD-L1-lnc 可作为肺腺癌的检测指标，预测患者的愈后情况。 9 可变剪接与肺癌中外泌体形成 外泌体是细胞外囊泡的一部分，其可被脂质双分子层包裹，直径在 40-160 纳米，大多数真核细胞可形成外泌体 [86] 。外泌体在肿瘤中的功能也被越来越多 地报道，其在肿瘤的发展、转移和免疫等方面皆发挥着重要的作用 [87] 。鉴于 RNA 可变剪接的普遍性，且外泌体中包含多种 RNA，可变剪接对于外泌体的调控同 样引起了人们的重视。如 HBS1L 的短剪接形式，其和外泌体及 SKI 复合物的形 成密切相关 [88] 。但是外泌体中是否包含经过可变剪接而产生的 RNA 分子，目前 尚不清楚。 10 可变剪接与肺肿瘤微环境 肿瘤微环境(Tumor microenvironment，TME)是一个复杂且不断发展的过 程。除了基质细胞、成纤维细胞和内皮细胞，TME 还包含诸多先天性和适应性 免疫细胞。由于 TME 中细胞组成的复杂性，血管生成有限且分化较差，导致了 营养、氧气输送和废物清理效率低下 [89] 。TME 与肿瘤诸多生命活动关系密切， 如肿瘤转移 [90] 、肿瘤细胞耐药 [90] 、放化疗 [91,92] 、免疫治疗等 [90,93] 。此外，越来 越多的证据表明， 可变剪接同样可以参与肿瘤微环境的调控。 可变剪接在乳腺癌、 胃癌、恶性胶质瘤、肺癌等恶性肿瘤微环境中的功能越来越多地被报道 [94][95][96][97][98]…”